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Astrocytes—the star-shaped cells that support neurons in the brain—seem two-faced. While they can trigger harmful neuroinflammation, astrocytes also secrete molecules that may help curb that destruction. Two papers in this week’s Journal of Neuroscience describe examples of such heroics. Researchers led by Inhee Mook-Jung at Seoul National University College of Medicine, South Korea, posit that ATP released by astrocytes stems synaptic damage induced by Aβ peptides. And in a second paper, Flavia Trettel of the University of Rome, Italy, and colleagues present a mechanism whereby neuron-astrocyte crosstalk driven by a transmembrane chemokine protects against excitotoxic neuronal death. Further work is needed to determine if the findings hold up in vivo, but the data lend hope to prospects of harnessing protective astrocytic factors for the treatment of neurodegenerative disease.

Β-amyloid peptides stimulate astrocytes to unleash a slew of chemicals, yet it has been hard to discern the impact of these gliotransmitters on surrounding neurons. Mook-Jung’s team focused on one—adenosine triphosphate (ATP)—and explored its effects on Aβ-mediated neuronal dysfunction in a series of in-vitro experiments. They first demonstrated that synthetic, commercially available Aβ42 peptide triggers ATP release when added to cultures of primary mouse astrocytes or U373 human astroglioma cells. However, because it is hard to collect pure astrocyte-derived ATP in reasonable amounts, Mook-Jung said, subsequent experiments tested the effect of exogenous ATP on Aβ-treated neurons.

In these assays, first author Eun Sun Jung and colleagues found that ATP protected against Aβ toxicities—namely, loss of dendritic spines, decreased hippocampal long-term potentiation, and reduced levels of synaptic molecules, such as the NMDA receptor 2A subunit and PSD-95. Furthermore, the researchers determined that ATP exerts these protective effects through P2 type-purinergic receptor signaling, because a P2 antagonist blocked the ATP-induced drop in synaptic proteins. Purinergic receptors mediate cellular functions such as vascular responses and apoptosis. P2 receptors are preferentially activated by ATP.

Whereas other studies have examined how glial factors affect neurons, “this is one of the first to look at ATP alone,” Mook-Jung told ARF. And though the research does not prove that the neuronal benefits come from astrocyte-derived ATP, “it raises the possibility that a glial source of ATP—if one could harness it—could provide protection,” said Philip Haydon, Tufts University School of Medicine, Boston, Massachusetts, in an interview with ARF. “The key thing is they show a simple molecule could have these protective effects.”

But the situation is complex. Francesco Di Virgilio and colleagues at the University of Ferrara, Italy, reported that in AD mouse models, microglia, the other major non-neuronal cell in the brain, release ATP that induces inflammation (Sanz et al., 2009; see Di Virgilio comment below). Whether the findings apply in vivo remains to be seen. Future studies could examine whether selectively blocking ATP release from astrocytes worsens disease in an AD mouse model, Haydon suggested (see full comment below).

The second paper extends a chemokine theme. Prior research, led by coauthor Cristina Limatola, uncovered a mode of neuron-glia communication whereby neurons churn out fractalkine (CX3CL1) that signals to fractalkine receptor (CX3CR1) on microglia, which then make adenosine that signals back to neurons, protecting them from glutamate-induced death (Lauro et al., 2008; Lauro et al., 2010).

In the present study, first author Maria Rosito and colleagues turn their attention toward a related chemokine, CXCL16, and its receptor CXCR6. Both appear in astrocytes, microglia, and neurons. Like fractalkine, CXCL16 is a transmembrane chemokine that is released from the membrane by metalloproteinases such as ADAM10 and ADAM17. These same enzymes drive non-amyloidogenic processing of amyloid precursor protein (APP) by cutting smack dab within its amyloid-β fragment, thus preventing formation of AD-associated peptides.

Through a series of in-vitro experiments, the researchers worked out a molecular pathway for CXCL16-mediated neuron-glia crosstalk. They spiked excess glutamate into mixed cultures of neuronal and glial cells, triggering neuronal death in a manner relevant to a variety of situations including brain injuries, stroke, and neurodegenerative disease. However, when the same cells encountered soluble CXCL16 as well, it dose-dependently protected against cell death.

CXCL16 seems to protect by specifically signaling to receptors on astrocytes, since the benefits persisted even when microglia activation in hippocampal neuronal cultures was blocked pharmacologically. Intriguingly, these scientists also linked neuroprotection to an ATP relative. By removing all extracellular adenosine or specifically blocking A3R adenosine receptors, they blocked CXCL16 protection. The team also determined that CXCL16 spurs astrocytes to secrete the chemokine CCL2 (aka monocyte chemoattractant protein-1 or MIP-1), and that neutralizing CCL2 antibodies reduces the neuroprotection.

“They’ve clearly done a nice piece of mechanistic biology,” said Terrence Town of the University of California, Los Angeles. He wonders, though, how much of the neuroprotection will pan out in vivo. Town cited recent mouse studies by Richard Ransohoff and Bruce Lamb of the Cleveland Clinic Foundation, Ohio, showing that microglial fractalkine signaling has opposing effects on the two hallmark pathologies of AD, Aβ plaques and neurofibrillary tangles. Knocking out the microglial fractalkine receptor in APPPS1 (which develops rapid Aβ pathology) and A-R1.40 transgenic mice (which develop milder pathology) reduced plaque load, compared to AD mice with normal microglia. Yet loss of the fractalkine receptor intensified tau hyperphosphorylation in a transgenic mouse model of human tauopathy (see ARF related news story). This makes it hard to determine whether microglial fractalkine signaling is ultimately harmful or beneficial. In another study, lack of the microglial fractalkine receptor prevented neurodegeneration in triple transgenic AD mice, suggesting that fractalkine signaling is not neuroprotective (ARF related news story on Fuhrmann et al., 2010).

Ransohoff found the present study “very novel and interesting,” but agreed that in-vivo studies are needed “to see whether any of this work relates to cells in their native context,” he told ARF.—Esther Landhuis

Comments on News and Primary Papers

This is an intriguing study showing that exogenous ATP acting
through P2 receptors can attenuate deleterious actions of Aβ42 on
neuronal properties, including reductions in spine density, synaptic
protein expression, and synaptic plasticity. Because ATP is known to be
a gliotransmitter released from astrocytes, and since the authors show,
at least in culture, that Aβ42 stimulates astrocytic ATP release, they
suggest that astrocyte-derived ATP may protect against Aβ42-induced
impairments in synaptic plasticity. This observation will need to be
verified in more intact systems, and it will be necessary to
selectively inhibit ATP release from astrocytes and determine
consequences on the progression of the neuronal and synaptic
impairments in Alzheimer’s mouse models.

Alzheimer’s disease (AD) is characterized by irreversible neuronal
damage as a result of a direct effect of Aβ on neurons, as
well as a profound subversion of neuron-glia interactions.

The paper by Sun Jung and coworkers describes a novel mechanism by
which neuron-glia, or rather glia-neuron, interaction might modulate
the neurotoxic effect of Aβ. They identify ATP as the
astrocyte-derived messenger that attenuates Aβ’s injurious
effects. The finding that Aβ triggers ATP release from
astrocytes is not novel per se, but the observation that
co-stimulation with ATP protects neurons from the damaging effect of
β amyloid is. The role of ATP as a neuro- and gliotransmitter is
long known. More recently, a trophic activity for ATP has also been
described. This paper reports a good example of this neuroprotective
activity.

However, it should be stressed that ATP released in the central nervous system is likely to have a dual role: as a neurotrophic factor and a proinflammatory
mediator. Whether ATP acts as the former or the latter depends on the
concentration, the glial cell type involved, and the P2 receptor activated.
In order to place the paper by Sun Jung et al. in the proper context,
we should keep in mind that Aβ can also trigger ATP release
from microglia, but in this case, rather than having a protective
effect, ATP aggravates Aβ neurotoxicity by triggering IL-1
release and thus inducing inflammation. In this respect, a key piece of
information missing from this paper is the lack of
identification of the P2 receptor subtypes responsible for the
neuroprotective effect. They use PPADS as an inhibitor, but this
molecule has a broad selectivity and does not allow identification of
the receptor(s) involved. This is crucial in my opinion because, if
one wishes to take inspiration from these observations to develop an
innovative pharmacological treatment, identification of the P2
receptor(s) is mandatory. Furthermore, these findings raise obvious
questions: If Aβ triggers a protective ATP release, why is this not sufficient to prevent Aβ neurotoxicity? Is this protective
effect relevant in vivo? Finally, a better model to check for the
protective ATP effect would be neuron-astrocyte co-cultures. This
experimental system allows one to explore astrocyte-neuron interactions in
a more physiological setting.